Olefin metathesis catalysis is a powerful technology, which in recent years has received tremendous attention as a versatile method for the formation of carbon-carbon bonds and has numerous applications in organic synthesis and polymer chemistry (R. H. Grubbs, Handbook of Metathesis, Vol. 2 and 3; Wiley VCH, Weinheim, 2003). The family of olefin metathesis reactions includes ring-closing metathesis (RCM), cross metathesis (CM or XMET), ring-opening metathesis polymerization (ROMP), and acyclic diene metathesis polymerization (ADMET). The success of olefin metathesis stems from the development of several well-defined transition metal complexes, such as the Schrock molybdenum catalysts and the Grubbs ruthenium and osmium catalysts (see, e.g., Schrock (1999) Tetrahedron 55, 8141-8153; Schrock (1990) Acc. Chem. Res. 23, 158-165; Grubbs et al. (1998) Tetrahedron 54, 4413-4450; Tmka et al. (2001) Acc. Chem. Res. 34, 18-29; Grubbs, Handbook of Metathesis, Vol. 1; Wiley VCH, Weinheim, 2003). Following the discovery of these complexes, a significant amount of olefin metathesis research has focused on tuning the ruthenium and osmium carbene catalysts in order to increase their activity, selectivity, and/or stability. The most common strategy has involved the replacement of mono-dentate ligands with other mono-dentate ligands to provide the catalytic complexes with new and useful properties.
The original breakthrough ruthenium catalysts were primarily bisphosphine complexes of the general formula (PR3)2(X)2M═CHR′ wherein M is ruthenium (Ru) or osmium (Os), X represents a halogen (e.g., Cl, Br, or I), R represents an alkyl, cycloalkyl, or aryl group (e.g., butyl, cyclohexyl, or phenyl), and R′ represents an alkyl, alkenyl, or aryl group (e.g., methyl, CH═C(CH3)2, phenyl, etc.) (see Nguyen et al. (1992) J. Am. Chem. Soc. 1992, 114, 3974-3975; Schwab et al. (1995) Angew. Chem., Int. Ed. 34, 2039-2041; Schwab et al. (1996) J. Am. Chem. Soc. 118, 100-110). Examples of these types of catalysts are described in U.S. Pat. Nos. 5,312,940, 5,969,170 and 6,111,121 to Grubbs et al. While such complexes are capable of catalyzing a considerable number of olefin metathesis transformations, these bisphosphine complexes can exhibit lower activity than desired and, under certain conditions, can have limited lifetimes.
More recent developments in the field have led to increased activity and stability by replacing one of the phosphine ligands with a bulky N-heterocyclic carbene (NHC) ligand (Scholl et al. (1999) Organic Letters 1, 953-956) to give complexes of the general formula (L)(PR3)(X)2Ru═CHR′, wherein L represents an NHC ligand such as 1,3-dimesitylimidazole-2-ylidene (IMes) and 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene (sIMes), X represents a halogen (e.g., Cl, Br, or I), R represents an alkyl, cycloalkyl, or aryl group (e.g., butyl, cyclohexyl, or phenyl), and R′ represents an alkyl, alkenyl, or aryl group (e.g., methyl, CH═C(CH3)2, phenyl, etc.). Representative structures include complex A (ibid.), complex B (Garber et al. (2000) J. Am. Chem. Soc. 122, 8168-8179), and complex C (Sanford et al. (2001) Organometallics 20, 5314-5318; Love et al. (2002) Angew. Chem., Int. Ed. 41, 4035-4037):

Unlike prior bisphosphine complexes, the various imidazolylidine catalysts effect the efficient formation of trisubstituted and tetrasubstituted olefins through catalytic metathesis. Examples of these types of catalysts are described in PCT publications WO 99/51344 and WO 00/71554. Further examples of the synthesis and reactivity of some of these active ruthenium complexes are reported by Fürstner et al. (2001) Chem. Eur. J. 7, No. 15, 3236-3253; Blackwell et al. (2000) J. Am. Chem. Soc. 122, 58-71; Chatterjee et al. (2000) J. Am. Chem. Soc. 122, 3783-3784; Chatterjee etal. (2000) Angew. Chem. Int. Ed. 41, 3171-3174; Chatterjee et al. (2003) J. Am. Chem. Soc. 125, 11360-11370. Further tuning of these catalysts led to even higher activity by using bulkier imidazolylidine ligands such as 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidenes (Dinger et al. (2002) Adv. Synth. Catal. 344, 671-677) or electron deficient phosphine ligands such as fluorinated aryl phosphines (Love et al. (2003) J. Am. Chem. Soc. 125, 10103-10109).
Another example of ligand substitution that has led to enhanced catalyst activity is the replacement of the phosphine ligand in the (L)(PR3)(X)2M═CHR′ complexes with one or two pyridine-type ligands to give compounds of the general formula (L)(L′)n(X)2M═CHR′ wherein n=1 or 2, L represents an imidazolylidine ligand, L′ represents a pyridine (Py) or substituted pyridine ligand, X represents a halogen (e.g., Cl, Br, or I), and R1 represents an alkyl, alkenyl, or aryl group (e.g., methyl, CH═C(CH3)2, phenyl, etc.). These pyridine complexes are extremely fast-initiating and catalyze living ring-opening metathesis polymerizations (Choi et al. (2003) Chem. Int. Ed. 42, 1743-1746) as well as highly challenging processes such as olefin cross metathesis with acrylonitrile (Love et al. (2002) Angew. Chem. Int. Ed. 41, 4035-4037).
Yet another example of mono-dentate ligand substitution is the replacement of the halogen ligands with aryl-oxo ligands, which in one example has led to a catalyst with enhanced activity: (L)(L′)n(RO)2Ru═CHR′ wherein n=1, L represents an imidazolylidine ligand, L′ represents a pyridine ligand, R represents a fluorinated aryl group, and R′ represents an alkyl, alkenyl, or aryl group (Conrad et al. (2003) Organometallics 22, 3634-3636).
A different strategy to tune olefin metathesis catalysts involves linking two of the ligands that are attached to the metal center. Of particular interest are the chelating carbene species reported by Hoveyda and others (Gaber et al. (2000) J. Am. Chem. Soc. 122, 8168-8179; Kingsbury et al. (1999) J. Am. Chem. Soc. 121, 791-799; Harrity et al. (1997) J. Am. Chem. Soc. 119, 1488-1489; Harrity et al. (1998) J. Am. Chem. Soc. 120, 2343-2351). These catalysts are exceptionally stable and can be purified by column chromatography in air.
Fewer efforts to differentiate catalyst performance and regulate olefin metathesis reactions have focused on the development of charged ruthenium metal complexes. Several groups have demonstrated cationic compounds of the general type [(L)(L′)(X)Ru═(C)n═CRR′]+ (L and L′ are any of a variety of neutral electron donors, X is typically halide, and n=0,1,2. . .). In U.S. Pat. No. 6,590,048, Fürstner teaches the use of cationic vinylidene, allylidene and higher cumulene complexes for a variety of olefin metathesis reactions. In U.S. Pat. No. 6,500,975, Schwab and coworkers describe the use of cationic ruthenium alkylidyne complexes and their use in the metathesis of electron poor olefins. In U.S. Pat. No. 6,225,488, Mukerjee et al. teach the use of cationic (bisallyl) vinylidene complexes of ruthenium or osmium for the ring-opening metathesis polymerization of norbornene derivatives. Other cationic Group 8 metathesis catalysts have been described by Jung et al. (2001) Organometallics 20:2121; Cadiemo et al. (2001) Organometallics 200:3175; De Clereq et al. (2002) Macromolecules 35:8943; Bassetti et al. (2003) 22:4459; Prühs et al. (2004) Organometallics 23:280; and Volland et al. (2004) Organometallics 23:800. These are typically derived from abstraction of an anionic ligand from the coordination sphere of a neutral metal precursor. Alternatively, a cationic ligand in a neutral complex may be replaced by a neutral ligand resulting in cationic metal complexes. Distinct from the above-described complexes, Audic et al. (2003) J. Am. Chem. Soc. 125:9248 makes use of olefin cross metathesis to link an imidazolium salt to the carbene moiety of a Grubbs or a Grubbs-Hoveyda catalyst precursor. The immediate coordination sphere of the resulting complexes remains intentionally unchanged, but the distal imidazolium salt confers solubility to the catalyst precursor in certain ionic liquids . These efforts were directed to the development of ionic liquid “supported” catalysts to facilitate catalyst recycle.
As will be discussed in further detail infra, the root of the lower activities of the some of the Grubbs catalysts, which may be generically denoted as X2(L)(L′)Ru═C(H)R, lies in their mode of initiation and the accessibility of the reactive species, the 14-electron alkylidene X2(L)Ru═C(H)R formed upon reversible dissociation of L′. Most of the improvements to the Grubbs “first generation” catalysts, e.g., Cl2(PCy3)2Ru═C(H)Ph (Cy=cyclohexyl), are modifications that either encourage loss of L′ (Love et al. (2003) J. Am. Chem. Soc. 125:10103) or reduce the tendency of Cl2(L)Ru═C(H)R to re-capture the liberated L′ (Sanford et al. (2001) J. Am. Chem. Soc. 123:6543) which competes with the olefin substrate for the unsaturated metal center in Cl2(L)Ru═C(H)R. Alternatively, Hoveyda had developed a series of catalysts in which L′ is a loosely chelating group associated with the carbene ligand that is removed upon the first metathesis event. See Kingsbury et al. (1999) J. Am. Chem. Soc. 121:791; Hoveyda (1999) J. Am. Chem. Soc. 121:791; and Garber et al. (2000) J. Am. Chem. Soc. 122:8168.
Despite these advances there remains a need for olefin metathesis catalysts that are highly active as well as stable to air and moisture, thermally stable, and tolerant of functional groups on the olefin substrates. Ideal catalysts would also be “tunable” with regard to activity, including initiation time and substrate conversion rate.